Substance-use disorders produce addiction and brain damage for which there is no reliable successful therapy, mainly due to lack of understanding of its pathobiology. Dependence upon drugs of addiction causes major health problems worldwide. For example, alcohol abuse and alcohol dependence can cause liver, pancreatic and kidney disease, heart disease, increased incidence of many types of cancer, insomnia, depression, anxiety, and even suicide. Nicotine addiction is linked to disease states such as leukemia, cataracts, and pneumonia; it is the cause of about one-third of all cancer deaths, the foremost of which is lung cancer. Another major health problem is caused by cocaine abuse. Physical effects of cocaine use include constricted blood vessels, dilated pupils, and increased temperature, heart rate, and blood pressure. It has been shown that many aspects of drug abuse and dependence involve changes in glutamate neurotransmission.
It has been realized that glutamate plays a central role in processes underlying the development and maintenance of addiction (Tzschentke, T. M. and W. J. Schmidt, Glutamatergic mechanisms in addiction. Mol Psychiatry, 2003. 8(4): p. 373-82). These processes include reinforcement, sensitization, habit learning and reinforcement learning, context conditioning, craving and relapse. It has been known that many substances, such as alcohol, cocaine, nicotine, ketamine, amphetamine and opiate, are able to promote the elevation of extracellular glutamate levels (Ding, Z. M., et al., Alcohol drinking and deprivation alter basal extracellular glutamate concentrations and clearance in the mesolimbic system of alcohol-preferring (P) rats. Addict Biol, 2013. 18(2): p. 297-306; Williams, J. M. and J. D. Steketee, Cocaine increases medial prefrontal cortical glutamate overflow in cocaine-sensitized rats: a time course study. Eur J Neurosci, 2004. 20(6): p. 1639-46; Saellstroem Baum, S., et al., Nicotine stimulation on extracellular glutamate levels in the nucleus accumbens of ethanol-withdrawn rats in vivo. Alcohol Clin Exp Res, 2006. 30(8): p. 1414-21; Moghaddam, B., et al., Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci, 1997. 17(8): p. 2921-7; Del Arco, A., et al., Amphetamine increases the extracellular concentration of glutamate in striatum of the awake rat: involvement of high affinity transporter mechanisms. Neuropharmacology, 1999. 38(7): p. 943-54; and Peters, J. and T. J. De Vries, Glutamate mechanisms underlying opiate memories. Cold Spring Harb Perspect Med, 2012. 2(9): p. a012088). However, the mechanism of substance-increased extracellular glutamate levels is poorly understood.
Although alcohol has been determined to be the inhibition of glutamatergic neurotransmission by antagonizing N-methyl-D-aspartate (NMDA) receptors, it has been demonstrated that chronic alcohol exposure induced the upregulation of NMDA receptors that results from chronic inhibition of glutamate transmission as a compensatory mechanism (Gonzales, R. A. and J. N. Jaworski, Alcohol and glutamate. Alcohol Health Res World, 1997. 21(2): p. 120-7). In addition, chronic alcohol exposure also increases extracellular glutamate levels and enhances NMDA sensitivity in brain of alcohol dependence or withdrawal, suggesting glutamate-mediated excitotoxicity offers a plausible mechanism for some of the neuronal losses and cognitive deficits associated with chronic alcoholism. In addition, it can be reasonably speculated that glutamate-mediated excitotoxicity also plays a role in other substances-induced neuron loss and consequently psychosis due to the elevation of extracellular glutamate.
The cystine-glutamate antiporter or system xc− is a membrane-bound Na+-independent amino acid transporter that is structurally composed of a heavy chain subunit common to all amino acid transporters, 4F2hc, and a light chain specific subunit, xCT (Bridges, R. J., N. R. Natale, and S. A. Patel, System xc(−) cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharmacol, 2012. 165(1): p. 20-34 and Sato, H., et al., Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. J Biol Chem, 1999. 274(17): p. 11455-8). The system xc− exchanges intracellular glutamate for extracellular cystine, thereby supporting intracellular glutathione (GSH) synthesis as well as nonvesicular glutamate release. Therefore, most of studies focused on its role on oxidative stress in cancer or other diseases (Buckingham, S.C., et al., Glutamate release by primary brain tumors induces epileptic activity. Nat Med, 2011. 17(10): p. 1269-74 and Albrecht, P., et al., Mechanisms of oxidative glutamate toxicity: the glutamate/cystine antiporter system xc− as a neuroprotective drug target. CNS Neurol Disord Drug Targets, 2010. 9(3): p. 373-82). However, recent results derived from xc− knockout mice indicate that loss of system xc− does not induce oxidative stress but decreases extracellular glutamate in brain, suggesting system xc− is an important source of extracellular glutamate involved in glutamatergic transmission and glutamate-mediated excitotoxicity (De Bundel, D., et al., Loss of system x(c)− does not induce oxidative stress but decreases extracellular glutamate in hippocampus and influences spatial working memory and limbic seizure susceptibility. J Neurosci, 2011. 31(15): p. 5792-803).
The dysregulation of system xc− has been linked with addiction because the reduction in extracellular glutamate after chronic treatment with either cocaine or nicotine resulted from reduced system xc− activity and levels of xCT expression in the accumbens (Baker, D. A., et al., Neuroadaptations in cystine glutamate exchange underlie cocaine relapse. Nat Neurosci, 2003. 6(7): p. 743-9; Knackstedt, L. A., et al., The role of cystine-glutamate exchange in nicotine dependence in rats and humans. Biol Psychiatry, 2009. 65(10): p. 841-5). Moreover, the restoration of system xc− activity by its activator N-acetylcysteine (NAC) prevents reinstated cocaine or nicotine seeking behaviors. However, the period of system xc− downregulation has not been directly determined in these mice. Recent studies demonstrated that the expression of system xc− subunit xCT in brain was upregulated in alcohol dependence mice but downregulated in alcohol withdrawal rats (Peana, A. T, G. Muggironi, and F. Bennardini, Change of cystine/glutamate antiporter expression in ethanol-dependent rats. Front Neurosci, 2014. 8: p. 311), suggesting a dynamic change in xCT expression and its activity during addiction. Besides, system xc− is not the only target for NAC and all pharmacological inhibitors commonly used to study system xc− activity have off-target effects (Lewerenz, J., et al., The cystine/glutamate antiporter system x(c)(−) in health and disease: from molecular mechanisms to novel therapeutic opportunities. Antioxid Redox Signal, 2013. 18(5): p. 522-55). These issues raise the uncertain role of system xc− in addiction.